Embolic compositions

ABSTRACT

Described herein are compositions comprising, a polymer; a non-physiological solution; and a visualization agent; wherein the polymer is soluble in the non-physiological solution and insoluble at physiological conditions. Methods of preparing the compositions are disclosed as well as methods of using these compositions to treat vascular conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/687,263, filed Aug. 25, 2017, which claims the benefit of U.S.provisional patent application No. 62/380,317, filed Aug. 26, 2016, theentire disclosure of each of which is incorporated herein by reference.

FIELD

The present invention relates generally to vascular treatmentcompositions and methods of using these compositions to treat vascularconditions. The compositions can comprise a polymer(s) that transitionsfrom a liquid to a solid upon being subjected to physiologicalconditions.

BACKGROUND

Embolization is widely used to treat vascular malformations, such asaneurysms, arteriovenous malformations, fistulas, and tumors. Thesemalformations can be treated with a variety of different products,including metallic coils, polymer-metal hybrid coils, microparticles,and foams. However, there remains a need for products that can minimizerisks associated with embolization.

SUMMARY

Polymeric compositions are described which comprise: a biocompatiblepolymer, a visualization agent, and a non-physiological solution;wherein the biocompatible polymer is soluble in the non-physiologicalsolution and insoluble at physiological conditions. In some embodiments,the visualization agent is integrated, e.g., chemically integrated, intothe biocompatible polymer. In other embodiments, the visualization agentis associated with the biocompatible polymer. In other embodiments, thevisualization agent may not be integrated into the biocompatiblepolymer. In some embodiments, the polymer need not be biocompatible.

In some embodiments, the solubility change from non-physiological tophysiological conditions can be instantaneous. The solubilized polymercan become an insoluble mass instantaneously. Instantaneous can be inless than about 0.1 s, less than about 0.5 s, less than about 1 s, orless than about 5 s.

Methods of using polymeric compositions are also described. In oneembodiment, methods are described comprising injecting through adelivery device into a physiological environment a liquid emboliccomposition. The liquid embolic composition can comprise a biocompatiblepolymer, a visualization agent, and a non-physiological solution,wherein the biocompatible polymer precipitates when it reaches thephysiological conditions.

In one embodiment, methods are described comprising injecting through adelivery device into a vessel with physiological environment a liquidembolic composition. The liquid embolic composition can comprise abiocompatible polymer, a visualization agent, and a water-miscibleorganic solvent, wherein the biocompatible polymer precipitates when itreaches the physiological conditions and treats the vascular disorder.

In another embodiment, methods are described comprising providing aliquid embolic composition. The liquid embolic composition can comprisea biocompatible polymer, a visualization agent, and a non-physiologicalpH aqueous solution. The biocompatible polymer can be soluble in thenon-physiological pH aqueous solution and insoluble at physiologicalconditions. In one embodiment, a delivery device can be inserted into avessel and guided to an area in need of treatment wherein the area hasphysiological conditions. The liquid embolic polymer composition canthen be injected through the delivery device into the vessel at the areain need of treatment thereby immediately precipitating the polymer andforming a solid polymeric mass and treating the vascular condition.

In another embodiment, methods are described comprising providing aliquid embolic composition comprising a biocompatible polymer, avisualization agent, and a water-miscible organic solvent. Thebiocompatible polymer can be soluble in the organic solvent andinsoluble at physiological conditions. In one embodiment, a deliverydevice can be inserted into a vessel and guided to an area in need oftreatment. The liquid embolic polymer composition can then be injectedthrough the delivery device into the vessel at the area in need oftreatment thereby immediately precipitating the polymer and forming asolid polymeric mass and treating the vascular condition.

Additional features and advantages are described herein, and will beapparent from the following Detailed Description and figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an experimental apparatus for Example 1.

FIGS. 2A-2C illustrate a comparison of radiopacity of embolics withdifferent radiopaque materials. FIG. 2A illustrates radiopacity of PHIL20% w/w. FIG. 2B illustrates radiopacity of PHIL 20% w/w+iohexol 30%w/w. FIG. 2C illustrates radiopacity of PHIL 20% w/w+triiodophenol 30%w/w.

FIG. 3 illustrates pKa curves for primary amines.

FIG. 4 illustrates a solution of poly(4-vinylpyridine) injected into PBSat pH 7.4.

FIG. 5 illustrates a comparison of different embolic compositions withand without a radiopaque material.

FIG. 6 illustrates water addition impact on the viscosity of a 9% w/wembolic polymer containing 30% w/w Iohexol. Twenty percent wateraddition can cause the solution to gel and the viscosity was notmeasured. Therefore, a high bar was added to the figure for reference.

FIG. 7 illustrates a schematic of an embolic dilution using a DMSOmicrocatheter flush before embolic injection.

FIG. 8 schematically illustrates DMSO/Water co-solvent microcatheterflush before liquid embolic injection forming a semi-plug.

FIG. 9 is a movie still image capture of 9% w/w PLATO injection using a50/50 water/DMSO flush mixture.

DETAILED DESCRIPTION

Described herein generally are polymeric compositions. Thesecompositions can include biocompatible polymers and visualizationagents. In some embodiments, the biocompatible polymers can be solublein selected solvent systems and insoluble at physiological conditions orin a physiological solution/fluid in a selected solvent. In otherembodiments, the visualization agents can be an opacification agent(s)that can permit visualization in vivo. In other embodiments, thesolution can include a miscible solvent that can dissolve the polymer.In some embodiments, the miscible solvent can be a water misciblesolvent. In other embodiments, the miscible solvent can be a watermiscible organic solvent diluted with water. In certain embodiments, thepolymeric compositions can include a catheter flush solution. In someembodiments, the catheter flush solution can be a miscible organicsolvent and/or a miscible organic solvent diluted in water. In otherembodiments, the solution can include a non-physiological pH solvent.The compositions can be introduced through a delivery device in a liquidstate and transition to a solid state once in contact with aphysiological fluid.

When a polymer is soluble in solution, it can be easy to deploy througha delivery device, e.g. microcatheter, to a delivery site and/ortreatment site. However, once precipitated out of solution, a polymercan be much more difficult to deploy. For example, once precipitated, apolymer can in some instances be more difficult to deploy through adelivery device. As such, the compositions and methods described hereincan provide polymer treatment solutions to sites that would otherwisenot be easily administered to without being soluble prior to exiting adelivery device.

The compositions can comprise a solution at a non-physiologicalcondition (e.g. non-physiological pH). The solution can include apolymer soluble in the solution but insoluble at physiologicalconditions. In some embodiments, the solution can include a polymersoluble in a non-physiological pH aqueous solution but insoluble atphysiological conditions. In another embodiment, the polymer can besoluble in a water-miscible organic solvent but insoluble atphysiological conditions (e.g. water).

Physiological fluids can include, but are not limited to, blood, urine,saliva, mucous, vaginal fluid, seminal fluid, cerebral spinal fluid,sweat, plasma, bile, stomach acid, intestinal fluids, and the like.

A function of the biocompatible polymer, e.g. liquid embolic polymer,can be to precipitate when coming into contact with blood or otherphysiological fluid(s). If the pH of the physiological fluid is thesolubility trigger, the physiological pH can be a pH of about 7.0, about7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7 orabout 7.8, between about 7.0 and about 7.8, between about 7.1 and about7.7, between about 7.2 and about 7.6, or any value in a range bound byor between any of these values. The non-physiological pH can be a pHbetween about 1.0 and about 6.9, or about 2.0 and about 6.0, about 7.9and about 12.0, about 8.5 and about 10.0. Alternatively, if thesolubility trigger is solubility in a water miscible organic solvent andinsolubility at physiological conditions, any physiological environmentcan initiate the precipitation.

Precipitation of the polymer at physiological conditions can be used toocclude a biological structure. Control of the liquid embolic polymer'ssolubility can be achieved by selection of the composition of thepolymer. The polymer can be prepared with monomers having ionizablemoieties. In some embodiments, the polymers can be a reaction product oftwo different monomers, three different monomers, four differentmonomers, five different monomers, or more. In the case of a pHsensitive solubility trigger, a hydrophobic polymer can be constructedwith a minimum amount of ionizable moieties to render the polymersoluble in non-physiological pH solutions. The ratio of monomers withionizable moieties and other monomers can be dependent on the structureof the monomers and can be determined experimentally.

Monomers used to form the polymers, or otherwise termed embolic polymeror embolic, are described. Embolic materials and embolic formulationsincluding these monomers and polymers including these monomers are alsodescribed. Further, methods of making embolic monomers and embolicmaterials, and methods of using the monomers and embolic materials aredescribed. The embolics described can have increased radiopacity and/orenhanced physical properties when compared to conventional embolicmaterials.

Liquid embolic devices can be formed of organic soluble polymers. Theseorganic soluble polymers can precipitate upon solvent exchange withwater or other solvent, thus acting as an embolic agent when injectedintra-arterially or venously.

In some embodiments, embolic polymers can includehydroxyethylmethacrylate (HEMA), lactide, glycolide, polyvinyl pyridine(PVP), alkylalkylacrylate, alkylacrylate, acrylate, styrene, polyvinylalcohol (PVA), acrylamide, ethylene glycol, combinations thereof,co-polymers thereof, and the like.

In some embodiments, polymers and/or monomers described can include avisualization agent bonded to it. In one embodiment, a visualizationagent bonded to the polymer can be triiodophenol-lactide-glycolide(TIP).

In other embodiments, the visualization agent can be a water solublemolecule, which can include, but is not limited to, Iohexol anddiatrizoic acid.

In certain embodiments, the visualization agent is a water insolublemolecule, which can include, but is not limited to, triiodophenol orTIP.

In some embodiments, embolic polymers can includehydroxyethylmethacrylate (HEMA), triiodophenol-lactide-glycolide (TIP),polyvinyl pyridine (PVP), PVP-co-polybutylmethacrylate, andPVP-co-styrene, PVP-co-polyvinyl alcohol (PVA) or PVA-co-polyacrylamide.

In one embodiment, an embolic polymer can include about 60% w/w HEMA andabout 40% w/w TIP. In another embodiment, an embolic polymer can includeabout 15% w/w HEMA and about 85% w/w TIP.

In some embodiments, a liquid embolic system includes a polymerdissolved in a solvent. The solvent used to dissolve the monomers can beany solvent that dissolves the desired monomers/polymers. Solvents caninclude water, methanol, acetonitrile, dimethyl formamide, dimethylsulfoxide, a co-solvent thereof, or a combination thereof. In oneembodiment, a liquid embolic system including a polymer dissolved in aco-solvent of water and dimethyl sulfoxide (DMSO) can precipitate whencontacted with water or blood.

Embolic polymers described herein can be pH sensitive and can be formedat least partially of polymers and/or monomers that are water soluble atone pH and insoluble when the pH is altered. Such materials may bebeneficial because they may not need organic solvents in order tofunction. Providing an embolic device that does not require an organicsolvent to deploy may be beneficial as many organic solvents can betoxic and/or not physiologically acceptable.

However, finding pH sensitive liquid embolic devices can be challengingbecause primary amine containing monomers for acid soluble polymers canhave drawbacks. In one embodiment, a primary amine is included, such asbut not limited to, aminoethyl methacrylate oraminopropylmethacrylamide, which has a pKa of about 10. As a solution pHfalls below 10, such amine containing polymers can become protonated;the lower the pH the more they become protonated inducing greater watersolubility to the polymer.

Thus, although primary amine containing embolic polymers can havesolubility at high pH, the pKa is much greater than physiological pH.The relationship of the amount of positive charged species and distancefrom the pKa is logarithmic on the ratio of the species present. Thisrelationship is shown mathematically by Equation 1.

$\begin{matrix}{{pH} = {{pKa} + {\log\frac{\left\lbrack {A -} \right\rbrack}{\lbrack{HA}\rbrack}}}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

FIG. 3 is a plot of this relationship for amine species. In this case ata pH of 9, a primary amine would be 90% positively charged, and at a pHof 8, 99% positively charged. Thus, a diminishing return may beexperienced for decreasing the solution pH as one gets further away fromthe pKa. Consequently, when using primary amines to solubilize apolymer, an extremely low solution pH (e.g., pH 3) may be required.

In one embodiment, an amine is included that requires a less acidicsolution and/or has a lower pKa. A subset of amine monomers that havethese criterions may be aromatic amines and may be included in theherein described polymers. Aromatic amines have pKa's ranging from about5.6 to about 6.0, inducing a greater solubility shift compared toprimary amines.

In one embodiment, an aromatic amine can be 1-vinylimidazole having apKa of about 6.0. This aromatic amine would be about 90% positivelycharged at a pH of 5, and only about 10% positively charged at a pH of7.

In comparison, a primary amine such as aminoethyl methacrylate (AEMA)can be 99.999% positively charged at a pH of 5 and 99.9% positivelycharged at a pH of 7. Some embodiments may include this amine.

In another embodiment, an aromatic amine can be 4-vinylpyridine.

In some embodiments, an aromatic amine monomer(s) can be combined withother hydrophilic or hydrophobic monomers to create a polymer whichwould have desired precipitation characteristics. Therein, the aromaticamine would induce the pH sensitivity, and a hydrophobic monomer wouldaid in the water precipitation and/or a hydrophilic monomer would aid insolubility.

Embolic compositions, in some embodiments, can include both hydrophilicand hydrophobic monomers incorporated into the polymer chain. Forexample, vinyl alcohol and hydroxyethylmethacrylate are hydrophiliccomponents which can be included in the herein described embolicpolymers. Because of the dual hydrophilic/hydrophobic nature of thepolymer backbone, a certain amount of water can be incorporated into theorganic solvent without causing precipitation.

In some embodiments, a co-solvent system can be used to dissolve embolicpolymers more efficiently. In one embodiment, the co-solvent system is awater-DMSO co-solvent system. In other embodiments, water:DMSO mixtureratios may range from 1:99, 5:95, 10:90, 15:85, 20:80, 25:75, 30:70,35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20,85:15, 90:10, 95:5, or 99:1.

In embodiments where the embolic polymer includes increased amounts ofHEMA, the embolic polymer may impart greater cohesiveness at the cost oflower radiopacity and/or higher viscosity. In order to offset thepotentially lower radiopacity, a contrast agent/radiopaque material canbe added. However, in some embodiments, addition of a radiopaquematerial can increase the viscosity; this is illustrated in FIG. 5.

In some embodiments, to counteract an increased viscosity, a reducedamount of embolic polymer can be used to allow for syringe injection.

In other embodiments, viscosity of an embolic polymer can be reduced byaddition of water to the solvent. In one embodiment, an emboliccomposition including about 6% w/w polymer and 30% Iohexol has similarviscosity to a 35% w/w embolic polymer concentration, the precipitationperformance of the material may be poor. In one embodiment, theviscosity of this embolic polymer can be reduced by the addition ofwater (FIG. 6).

In some embodiments, increasing the water content in the solvent from 0to 15% w/w can decrease viscosity. In one embodiment, when the waterconcentration exceeds about 20% w/w, the solution may begin to gel andnot flow.

When water can be added to the solvent, a co-solvent can expose apatient to less potentially harmful solvent. In one embodiment, whenDMSO is used as a solvent, a water-DMSO co-solvent system exposes apatient to less DMSO. Reducing the total DMSO burden on a patient mayreduce vasospasm and/or other toxic side effects from DMSO.

In some embodiments, water addition to the solvent can modulate theviscosity of the embolic by the amount of water incorporated into theformulation. Further, in other embodiments, water incorporation canchange how the polymer precipitates. For example, in one embodiment, anembolic in a solvent with no water would have a reduced viscosity beforeprecipitating (see FIG. 7), possibly allowing the liquid embolic to flowmore easily. In contrast, an embolic formulation with 15% w/w waterwould not have a reduction in viscosity before precipitation and maylead to more control over the embolic resulting from a reduced flow.

Embolic systems can include up to about 1% w/w, up to about 2% w/w, upto about 3% w/w, up to about 4% w/w, up to about 5% w/w, up to about 6%w/w, up to about 7% w/w, up to about 8% w/w, up to about 9% w/w, up toabout 10% w/w, up to about 15% w/w, up to about 20% w/w, up to about 25%w/w, up to about 30% w/w, up to about 35% w/w, up to about 40% w/w, orup to about 50% w/w water before the embolic polymer precipitates. Insome embodiments, the amount of water that an embolic solvent cancontain without the embolic polymer precipitating can be dependent onthe amount of HEMA; the more HEMA, the more water can be included in thesolvent.

In one embodiment, the embolic system can comprise about 85% w/w/l TIP,about 15% w/w HEMA, and about 20% w/w DMSO with up to about 5% w/wwater. In another embodiment, the embolic system can comprise about 40%w/w/TIP, about 60% w/w HEMA, and about 8% w/w DMSO with up to about 20%w/w water, or about 9% w/w DMSO with up to about 15% w/w water, or about10% w/w DMSO with up to about 15% w/w water. In yet another embodiment,the embolic system can comprise about 50% w/w/TIP, about 50% w/w HEMA,and about 7% w/w DMSO with up to about 7.0% w/w water, or about 7.5% w/wDMSO with up to about 7.5% w/w water, or about 8% w/w DMSO with up toabout 7.5% w/w water, or about 9% w/w DMSO with up to about 10% w/wwater.

In one embodiment, when the embolic is present at 35% w/w, the solventcan contain about 5% w/w water. In other embodiments, when the embolicincludes a higher HEMA concentration, the solvent can contain more thanabout 15% w/w water before precipitation.

A co-solvent system can also be used with an embolic system such asONYX® (Covidien). ONYX is a polyethylene vinyl alcohol based,non-adhesive liquid embolic agent used for the pre-surgical embolizationof brain arteriovenous malformations (bAVM).

A co-solvent system can also be used with embolic systems that utilizeparticulates for radiopacity. These particulates can include tantalum,tungsten, barium sulfate, etc rather than an incorporated TIP orcontrast agent.

In some embodiments, viscosity of the herein described embolic polymerscan be reduced when compared to a conventional embolic polymer. In otherembodiments, viscosity can be reduced, and the embolic polymer may beincreased. Such a combination may lead to a better precipitatingsolution.

In some embodiments, the embolic can be a precipitating hydrophobicinjectable liquid (PHIL). A PHIL material can include a polymer moleculecomprising triiodophenol-lactide-co-glycolide acrylate and HEMA.Triiodophenol is an iodine component that can be chemically bonded tothe co-polymer to provide fluoroscopic visualization.

As described herein, the embolic PHIL polymer can be dissolved in DMSOor another appropriate solvent to formulate a liquid version wherein thepolymer is dissolved. Generally, a higher polymer concentration in DMSO,a higher viscosity and a higher material radiopacity. In one embodiment,a PHIL with 25% w/w polymer and 75% w/w DMSO offers just adequateradiopacity. If the polymer concentration is lowered, radiopacity islowered, thereby creating unsafe conditions and a possibly unusableembolic polymer solution. However, a formulation that if viscosity canbe reduced, the embolic polymer can travel more distal for deliverywhich may be desirable.

In some embodiments, monomers used to form the herein described embolicpolymers can include triiodophenol-lactide glycolide acrylate.Production of this monomer can include a step of reacting triiodophenolwith lactide glycolide and acryloyl chloride. Generally, one molecule oftriiodophenol can be reacted with two molecules of lactide, one moleculeof glycolide, and one molecule of acryloyl chloride. A resulting monomercan have a molecular weight of 930 g/mol and have three atoms of iodine.Since iodine has a molecular weight of 126.9 g/mol, 380.7 g/mol of themonomer is attributed to iodine. Thus, the weight of iodine can accountfor about 40.7% of a monomer's weight.

In some embodiments, the amount of non-iodine components can be reducedduring monomer synthesis. In one embodiment, one molecule oftriiodophenol can be reacted with one molecule of lactide (instead oftwo) and one molecule of glycolide and one molecule of acryloylchloride. A resulting monomer can have a molecular weight of 786 g/molwith iodine now contributing the same three atoms, which increases theiodine concentration from about 40.7% to about 48% of the monomer'sweight.

In some embodiments, the embolics described herein can have aradiopacity that decreases over time. Such an embolic can include adegradable linkage between the iodine-containing group and the main bodyof the polymer. In one embodiment, this linkage can be alactide-glycolide linkage between the iodine-containing group and themain body of the polymer. In some embodiments, water may be unable toaccess the solid, hydrophobic polymer. Thus, functionality of PLGA maybe limited in the embolic molecule and reducing its percentage may havean impact on the embolic's properties in some embodiments.

In some embodiments, embolics are provided with an increased radiopacitywhen compared to conventional embolics. An increased radiopacity can beachieved by including a higher percentage of iodine in the monomer usedto form the embolic. In some embodiments, the percent of iodine in amonomer can be greater than about 42% w/w, greater than about 43% w/w,greater than about 44% w/w, greater than about 45% w/w, greater thanabout 46% w/w, greater than about 47% w/w, greater than about 48% w/w,greater than about 49% w/w, or greater than about 50% w/w.

If a monomer has a higher percent of iodine, it will increaseradiopacity for PHIL 25, 30 and 35.

In some embodiments, embolics are provided with a lower viscosity thanconventional embolics. This can potentially facilitate making PHIL 20 orPHIL 15 with acceptable radiopacity.

In some embodiments, embolics are provided with an increased cohesivitythan conventional embolics. In some embodiments, cohesiveness can beincreased by reducing the concentration of triiodophenol, increasing theconcentration of hydroxyethylmethacrylate (HEMA), or both.

Some embodiments provide embolic compositions having a viscosity of lessthan about 16 centistoke, less than about 15 centistoke, less than about14 centistoke, less than about 13 centistoke, less than about 12centistoke, less than about 11 centistoke, less than about 10centistoke, less than about 9 centistoke, less than about 8 centistoke,or less than about 7 centistoke. In one embodiment, an embolic isprovided with a viscosity less than about 16 centistoke.

In some embodiments, an embolic with a lower viscosity, e.g., less thanabout 16 centistoke, may be able to penetrate distally. A reducedviscosity liquid embolic can potentially penetrate further distallyduring an embolic procedure. This can be attributed to severalconcepts: 1) a reduced viscosity liquid embolic precipitate can haveless cohesion and therefore can be transported downstream further withblood flow during initial precipitation in comparison to a higherviscosity embolic and 2) a reduced viscosity liquid embolic can requireless injection force to fill voids/channels in an embolic cast andtherefore can penetrate more distally when compared with a more viscousliquid embolic.

Generally, physicians use diluted N-butyl-2-cyanoacrylate (nBCA) incases where distal penetration is required. The presently describedembolics and embolic compositions can provide flow control/arrestwithout fragmentation. This lack of fragmentation is unlike nBCA wherefragmentation is common.

In some embodiments, an embolic can be triiodophenol lactide-glycolide(monomer) bonded with HEMA. In one embodiment, the embolic includesabout 85% monomer and about 15% HEMA in the embolic molecule. The higherthe concentration of the embolic molecule in the solvent, the higher theviscosity and the higher the radiopacity. In some embodiments, thesolvent can be DMSO.

In some embodiments, an embolic monomer concentration of about 25% isabout the lowest concentration that can achieve acceptable radiopacity.The presently described embolics can achieve acceptable radiopacity withlower concentrations of embolic monomer. In some embodiments, embolicmonomers at concentrations of less than about 25%, less than about 20%,less than about 15%, or less than about 10% can achieve acceptableradiopacity.

Radiopacity of embolics described herein can be provided by radiopaquecompounds including iodinated compounds, metal particles, bariumsulfate, superparamagnetic iron oxide, gadolinium, tantalum, tungstencarbide, molybdenum, rhenium, or a combination thereof.

In one embodiment, an embolic is provided in a solvent and includesbarium sulfate.

In another embodiment, an embolic is provided in a solvent and includessuperparamagnetic iron oxide.

In another embodiment, an embolic is provided in a solvent and includesgadolinium.

In another embodiment, an embolic is provided in a solvent and includestungsten carbide.

In another embodiment, an embolic is provided in a solvent and includesmolybdenum.

In another embodiment, an embolic is provided in a solvent and includesrhenium.

In one embodiment, an embolic composition is provided including anembolic, dimethyl sulfoxide (DMSO), and a radiopaque material.

Other embodiments provide various components in syringes for delivery.For example, in one embodiment, an embolic composition is provided in afirst syringe, DMSO is provided in a second syringe, and a radiopaquemineral can be provided in a third syringe. The embolic composition inthe first syringe can include a radiopaque mineral in some embodiments.In other embodiments, the syringes can be provided as kits including asolvent compatible four-way stop cock. In one embodiment, the four-waystop cock can be a DMSO compatible four-way stop cock.

In some embodiments, radiopacity of embolics can be by adding one ormore solvent soluble radiopacifying molecules (excipient). In someembodiments, the solvent soluble radiopacifying molecules can be DMSOsoluble radiopacifying molecules. The excipient can be one that is alsosoluble in water. In some embodiments, the excipient can include aradiopacifying atom such as iodine, or bromine, but can also includeelements outside of group 17 of the periodic table.

In one embodiment, excipients can be diatrizoic acid based monomers.

In another embodiment, excipients can include iohexol or triiopdophenol.

Monomers and embolic materials described herein are substantiallynon-toxic.

Liquid embolic products generally use a solvent to pre-flush a deliverydevice to prevent premature precipitation of the liquid embolic. Someembolics use DMSO as the solvent and use it to pre-flush amicrocatheter. Again, this pre-flush allows the embolic to pass throughthe microcatheter without precipitating.

Unfortunately, a significant amount of mixing occurs between theflushing agent and the head of the embolic. FIG. 7 illustrates aschematic of how an embolic becomes diluted. As an embolic becomesdiluted as it travels down a delivery device (e.g., microcatheter), thediluted embolic becomes less cohesive and is difficult to visualizeusing fluoroscopy.

In some embodiments, to aid in preventing dilution, a microcatheter isflushed with a mixture of water and solvent. In one embodiment, theco-solvent can be water-DMSO. This co-solvent water-DMSO mixture canslightly solvate the embolic solution but can cause a smallsemi-precipitated plug or “semi-plug” to form. In embodiments where asemi-plug is desired, this semi-plug may not clog the delivery device.

In other embodiments, the formation of a semi-plug may reduce mixingeffects and diffusion of the solvent into the head of the embolicejection, preventing extensive dilution. FIG. 8 schematicallyillustrates this idea.

In some embodiments, water:DMSO mixture ratios may range from 1:99,5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50,55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, 95:5, or 99:1.In one embodiment, water:DMSO mixture ratios can be about 1-99% water.The water/DMSO mixture can also partially precipitate the liquid embolictherefore a hub adapter must be used with the microcatheter to minimizethe volume of the microcatheter hub.

Example 1

Iolhexol and triiodophenol were tested in embolic models underfluoroscopic guidance in conjunction with a lower viscosityprecipitating hydrophobic injectable liquid (PHIL 20 wt % in DMSO).Samples were prepared as follows:

Sample 1 PHIL 20% w/w FIG. 2A Sample 2 PHIL 20% w/w + iohexol 30% w/wFIG. 2B Sample 3 PHIL 20% w/w + triiodophenol 30% w/w FIG. 2C

To simulate the attenuation of a human body, six inches of acrylic wasused as a phantom. ANSI standards suggest using seven inches torepresent the abdomen/lumbar spine. However, as tested, a model composedof a pyrex dish (0.25″) and a PHIL test block (0.75″) added to theattenuation (FIG. 1).

Typical low resolution fluoroscopy was performed to simulate peripheralusage of the embolic (comparison shown in FIG. 2). A dramatic increasein radiopacity is seen for the embolic containing either iohexol ortriiodophenol. First, there is greater radiopacity of the embolic in themicrocatheter (Headway Duo). Secondly, there is greater radiopacity ofthe precipitated embolic.

Also, during the investigation, it was not apparent if any of theexcipient washed downstream.

Example 2

A monomer of triiodophenol-lactide-co-glycolide acrylate is prepared.The monomer is soluble in DMSO and is radiopaque due to its iodinecontent. Then, this monomer is dissolved in a PHIL polymer. Experimentsdemonstrated that 0.2-0.3 gm/ml of PHIL 20% w/w formulation in DMSOincreases radiopacity. This procedure is a physical dissolution processand may increase radiopacity without increasing viscosity in anequivalent fashion.

Also, experiments showed that dissolving the monomer in the PHIL polymeralso increases the cohesiveness of the embolus.

Some embodiments may require dissolving a short chain polymer in DMSO.An example may be a low viscosity polymer having 15-20% w/w of polymer.Such a short chain polymer can increase radiopacity and increasecohesiveness.

Other embodiments may require dissolving monomer into less radiopaqueand less cohesive systems (e.g., 25% w/w, 30% w/w, and 35% w/w PHIL). Bydissolving monomer in these formulations, increased radiopacity andcohesiveness may be obtained.

Example 3

Experiment 1: To a container was added 500 mg of acrylamide, 500 mg ofpolyvinly alcohol (PVA), and 500 mg of poly(4-vinylpyridine) in 4 mL ofsolution. Then 0.25 mL 1N HCl was added while subjecting to an 80° C.water bath. Then 0.25 mL portions of 1N HCl were added at 1 hr, 3 hr, 3hr 20 min (temperature of water bath was reduced to 37° C.), 4 hr 10min, 6 hr 10 min. After the final time point, the solution was left atroom temperature over a three-day weekend. After the weekend, the 500 mgof 60 kDA poly(4-vinylpyridine) had dissolved in the solution volume of5.25 mL. The other polymers did not dissolve.

Example 4

A water-DMSO co-solvent system was evaluated for peripheral compositionsof PHIL (PLATO). One iteration of PLATO includes 60% w/whydroxyethylmethacrylate (HEMA) and 40% w/wtriiodophenotriiodophenol-lactide-glycolide (TIP), opposed to PHIL whichis 15% HEMA and 85% TIP. The increased amount of HEMA imparted greatercohesiveness, in some circumstances, to the precipitated polymer at thecost of lower radiopacity and higher viscosity. An FDA approved contrastagent is added to augment the radiopacity, however upon addition theviscosity increases (FIG. 5). To counteract the increase in viscosity areduced amount of PLATO can be used to allow for syringe injection.

To test the implications of this phenomenon, PLATO with 0% water wastested and reduces in viscosity before precipitating as shown in FIG. 6,possibly allowing a liquid embolic to flow more distal. FIG. 6illustrates that water addition can impact the viscosity of 9 w/w %PLATO containing 30% w/w Iohexol. Water addition (20% w/w) caused thesolution to gel and the viscosity was not measured. In contrast, a PLATOformulation with 15% w/w water would not have a reduction in viscositybefore precipitation and may lead to more control over the liquidembolic.

HEMA may drive the amount of acceptable water in a co-solvent system.Experimentation shows that PHIL35 can contain up to 5% w/w water beforeprecipitation, thus a higher composition of HEMA appears to drive higheracceptable water concentrations. Furthermore, formulations of PLATO withhigher HEMA may also allow more than 15% w/w water before precipitation.

A 25% w/w solution of poly(4-vinylpyridine) purchased from Sigma Aldrich(472344) was dissolved in water with a final pH of 5.9. Then 50 μL ofsolution was injected into a vial of 5 mL of 10 mM PBS at pH 7.4. As thepolymer was injected the polymer precipitated as illustrated in FIG. 4.

Example 5 Co-Solvent Flush

A co-solvent flush was tested with a formulation of the peripheralliquid embolic (PLATO H). A 50/50 water/DMSO mixture was used to flushthe catheter before PLATO (9% w/w PLATO, 30% w/w Iohexol, 10% w/w water)was injected into a portal vein model. The first embolic to be ejectedfrom the catheter had greater cohesiveness and minimal washout comparedto a neat DMSO flush. FIG. 9 illustrates a still image captured of thefirst embolic ejection showing the semi-plug preventing dilution.

Unless otherwise indicated, all numbers expressing quantities ofingredients, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing embodiments (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments are described herein, including the best modeknown for carrying out the invention. Of course, variations on thosepreferred embodiments will become apparent to those of ordinary skill inthe art upon reading the foregoing description. Those of ordinary skillin the art are expected to employ such variations as appropriate, andembodiments described herein are to be practiced otherwise thanspecifically described herein. Accordingly, embodiments herein includeall modifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed unless otherwise indicated herein or otherwiseclearly contradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Further, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A composition comprising: a biocompatible polymer; asolvent; and a visualization agent; wherein the biocompatible polymer issoluble in the solvent and insoluble at physiological conditions, andthe composition has a viscosity of less than 16 centistokes.
 2. Thecomposition of claim 1, wherein the visualization agent is integratedinto or associated with the biocompatible polymer.
 3. The composition ofclaim 2, wherein the visualization agent istriiodophenol-lactide-glycolide (TIP).
 4. The composition of claim 1,wherein the physiological conditions include contact with aphysiological fluid including blood, urine, saliva, mucous, vaginalfluid, seminal fluid, cerebral spinal fluid, sweat, plasma, bile,stomach acid, intestinal fluids, or a combination thereof.
 5. Thecomposition of claim 4, wherein the physiological fluid has a pH ofabout 7.0.
 6. The composition of claim 4, wherein the physiologicalfluid has a pH of between about 7.0 and about 7.8.
 7. The composition ofclaim 1, wherein the solvent is a water miscible organic solvent.
 8. Thecomposition of claim 1, wherein the biocompatible polymer comprises anamine and the amine includes an amino group which is about 90%positively charged at a pH of 5 and about 10% positively charged at a pHof
 7. 9. The composition of claim 1, wherein the biocompatible polymerincludes hydroxyethylmethacrylate (HEMA), lactide, glycolide, polyvinylpyridine (PVP), 1-vinylimidazole, aminoethyl methacrylate (AEMA),4-vinylpyridine, alkylalkylacrylate, alkylacrylate, acrylate, styrene,polyvinyl alcohol (PVA), acrylamide, ethylene glycol, or combinationsthereof.
 10. The composition of claim 1, wherein the biocompatiblepolymer includes about 60% w/w HEMA and the visualization agent includesabout 40% w/w TIP.
 11. The composition of claim 1, wherein thebiocompatible polymer includes about 15% w/w HEMA and the visualizationagent includes about 85% w/w TIP.
 12. The composition of claim 1,wherein the solvent is water or a co-solvent of water and dimethylsulfoxide (DMSO).
 13. The composition of claim 1, further comprisingaminopropylmethacrylamide.
 14. The composition of claim 1, wherein thecomposition has a viscosity of less than 15 centistokes.
 15. Thecomposition of claim 1, wherein the composition has a viscosity of lessthan 14 centistokes.
 16. The composition of claim 1, wherein thebiocompatible polymer, together with the visualization agent, forms acohesive precipitate when insoluble at physiological conditions, andwherein the cohesive precipitate is more cohesive than a precipitateformed from an embolic composition comprising N-butyl-2-cyanoacrylate.17. The composition of claim 1, wherein the biocompatible polymer isformed from hydroxyethylmethacrylate monomers and aromatic aminemonomers.
 18. The composition of claim 1, wherein: the biocompatiblepolymer comprises about 15% w/w HEMA; the solvent comprises about 20%w/w DMSO with up to about 5% w/w water; and the visualization agentcomprises about 85% w/w TIP.
 19. The composition of claim 1, wherein:the biocompatible polymer comprises about 60% w/w HEMA; the solventcomprises about 8% w/w DMSO with up to about 20% w/w water, about 9% w/wDMSO with up to about 15% w/w water, or about 10% w/w DMSO with up toabout 15% w/w water; and the visualization agent comprises about 40% w/wTIP.
 20. The composition of claim 1, wherein: the biocompatible polymercomprises about 50% w/w HEMA; the solvent comprises about 7% w/w DMSOwith up to about 7.0% w/w water, about 7.5% w/w DMSO with up to about7.5% w/w water, about 8% w/w DMSO with up to about 7.5% w/w water, orabout 9% w/w DMSO with up to about 10% w/w water; and the visualizationagent comprises about 50% w/w TIP.
 21. The composition of claim 1,wherein: the biocompatible polymer comprises HEMA; the solvent comprisesa co-solvent of water and DMSO; and the visualization agent comprisesTIP.
 22. The composition of claim 1, wherein the composition has aviscosity of less than 13 centistokes.
 23. The composition of claim 1,wherein the composition has a viscosity of less than 12 centistokes.